Focal glomerulosclerosis (FGS) is often the end result of glomerular injury in humans and in experimental models of renal disease. FGS is frequently accompanied by marked proteinuria and is associated with progressive loss of renal function. Although mechanisms underlying the pathogenesis of FGS are not completely understood, several non-immunologic mechanisms have been implicated in the development of this lesion. It has been suggested, for example, that increased glomerular capillary pressures and flows may be fundamental to the development of FGS. On the other hand, recent studies from our laboratory have indicated that abnormal lipid metabolism may also be important in the pathogenesis of FGS. Although the exact mechanism is unclear, hypercholesterolemia and/or hypertriglyceridemia may be important in the development of glomerular injury in several animal models. Since both altered glomerular hemodynamics and lipid abnormalities contribute to the development of FGS, it is possible that these two factors may interact to cause more severe glomerular injury than either factor would cause alone. The proposed studies will investigate the possible synergistic interactions between altered glomerular hemodynamics, e.g., glomerular capillary hypertension, and abnormal lipid metabolism, e.g., hyperlipidemia, in the pathogenesis of FGS. Experimental maneuvers will be performed in rat models to induce alterations in glomerular hemodynamics in the presence and absence of hyperlipidemia. Renal ablation and adriamycin administration will be used to alter glomerular hemodynamics. Clofibric acid and dietary cholesterol supplementation will be used to lower and raise serum lipids, respectively, in models with normal and elevated glomerular pressures. Micropuncture techniques will be used to assess superficial nephron function and histologic evaluation of glomerular morphologic changes will be performed in all models. In this manner, the individual and combined effects of glomerular hemodynamic changes and lipid abnormalities on the pathogenesis of glomerular injury will be investigated.